Chemotherapy and immunotherapy using monoclonal antibodies have been relatively ineffective for the treatment of brain tumors, in part because of the blood-brain barrier (BBB). Enhanced dose intensity may be achieved by using osmotic BBB disruption (BBBD). During the current funding period, we have reported a multi-institutional series of 174 patients with primary central nervous system lymphoma (PCNSL) treated up front with methotrexate based chemotherapy and BBBD, with a 40% progression free survival at 5 years. This is among the best reported survival for PCNSL in the scientific literature. Improved survival appears to have been achieved without cognitive loss. In the current proposal we hope to improve these results using antibody based therapy in the two compartment model focusing on PCNSL for proof of principle; and to begin extending these concepts to the increasing problem of CNS breast cancer metastasis. In Aim 1, Mechanisms to improve brain tumor models, we will optimize hematogenous and intracerebrally implanted rat models of human brain tumors. In Aim 2, Characterization of immunotherapy treatment approaches and neurotoxicity in brain tumor models, the effect of immunotherapy, drug- and radio-immunoconjugates, and combination therapies will be assessed in a new rat intracerebral model of CNS lymphoma (CNSL) and in breast cancer brain metastases models. In aim 3 we will test whether treatment with the anti-VEGF mAb bevacizumab will prevent vascularization and tumor growth in micrometastatic brain tumors, as a mechanism to approach brain tumor prophylaxis. In aim 4 clinical trials of immunotherapy, radioimmunotherapy, and neurotoxicity in PCNSL will be conducted. Phase I and II clinical trials will investigate the safety and efficacy of rituximab with chemotherapy after BBBD in newly diagnosed and recurrent PCNSL, and radioimmunotherapy with yttrium-90 labeled anti- CD20 mAb ibritumomab tiuxetan (Zevalin). We also will characterize neurotoxicity in PCNSL patients who have survived 2+ years in complete response after chemotherapy +/- radiotherapy. In this renewal, we hope to continue to target the BBB using antibodies in a rare primary brain tumor to increase survival and decrease neurotoxicity by avoiding whole brain radiation; and to begin to translate this to CNS breast cancer metastasis, an increasingly common CNS malignancy. This proposal is in response to the Brain Tumor PRG sponsored by NINDS and NCI. PUBLIC HEALTH RELEVANCE: Characterize mechanisms to improve brain tumor models. Evaluate immunotherapy delivery and efficacy, and assess drug immunoconjugates, radioimmunoconjugates, and vascular targeting agents in preclinical brain tumor models. Perform clinical trials of antibody-based therapy and neurotoxicity in human primary central nervous system lymphoma.